Treatment Options for NTRK Fusion–Positive mCRC

Cathy Eng, MD, FACP, FASCO: The treatment options for this newly diagnosed patient with surgically unresectable disease based upon the fact that she reportedly has multiple liver metastasis, if her performance status is quite good, which it appears to be, with an ECOG [Eastern Cooperative Oncology Group] performance status of 1, obviously your treatment options may be to consider standard chemotherapy up front.

Secondly, you can consider immunotherapy, which now has been not only considered in the refractory setting of patients who have received at least 1 prior therapy, but as many of you know, it is already approved as per the NCCN [National Comprehensive Cancer Network] guidelines for patients who may not tolerate chemotherapy well. There are a lot of data, not only looking at single agent, but also doublet therapy with nivolumab and ipilimumab.

Then obviously the third option in this setting, which would be important if she tests positive for NTRK fusion, is to consider the role of one of the NTRK inhibitors.

Patients who are MSI [microsatellite instability] high are more likely to test positive for the NTRK fusion.

So although is it going to be less than 1% of all patients with colorectal cancer who will have an NTRK fusion, it’s reportedly between 25% and 30% of MSI-high patients who are NTRK positive.

In the setting of this patient, when I would want to consider utilizing larotrectinib, my preference would be to consider immunotherapy up front, and utilize one of the NTRK inhibitors at progression of disease. That would be my preference at this time, and that is because most of the literature regarding immunotherapy has a little bit more history and is longer-standing with greater median follow-up.

Are there any circumstances in which I would not want to provide targeted therapy in the setting of this driver mutation? I think based upon this case and based upon the literature that exists, my preference would not be to not pursue targeted therapy in this setting. I think is the most appropriate setting, in this patient who has an MSI-high tumor as well as an NTRK-positive fusion.

Transcript edited for clarity.

Case: A 68-Year-Old Woman With Metastatic NTRK Fusion-Positive Colon Cancer

Initial presentation

• A 68-year-old woman presented with a 3-month history of intermittent abdominal pain, and alternating constipation/diarrhea
• PMH/SH: hypertension and hypercholesterolemia, medically managed; colonoscopy at age 50 was unremarkable; never smoker; no family history of cancer
• PE: abdomen tender on deep palpation in the right lower quadrant

Clinical workup

• Labs: Hb 11.9, Hct 32%, MCV 75 fL, CEA 12.8 ng/mL
• Chest/abdominal/pelvic CT showed a 5-cm right sided bowl mass and multiple hepatic lesions, and regional lymphadenopathy
• Colonoscopy revealed a 5-cm mass in the ascending colon, biopsy was taken
• Pathology: grade 3 poorly differentiated adenocarcinoma, with invasion of the submucosa
• Biomarkers: KRAS-wt, NRAS-wt, BRAF-, NTRK+; MSI-H
• Stage TXNXM1; ECOG PS 1